Compositions for the control of hyperlipidemia

ABSTRACT

The invention provides pharmaceutical compositions comprising hypolipidemically active derivatives of 1,2,4-triazolidine-3,5-diones, 1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones, and 1,3,5-triazine-2,4(1H,3H)-diones in a pharmaceutically acceptable carrier for treating hyperlipidemia in mammals, particularly humans.

FIELD OF THE INVENTION

The present invention relates to compositions having hypolipidemicactivity and methods for their use in controlling hyperlipidemia inmammals. Specifically, the present invention is directed to methods forcontrolling hyperlipidemia by treating mammals, especially humans, witha class of hypolipidemic agents selected from1,2,4-triazolidine-3,5-diones,1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones and1,3,5-triazine2,4(1H,3H)-diones.

BACKGROUND OF THE INVENTION

Cholesterol is commonly found in all the tissues and blood of mammals,especially humans. Manufactured in the liver and other cells as asubstrate for other steroids and membrane synthesis; cholesterol is anormal constituent of bile. As will be appreciated, many familiar foodscontain cholesterol, with some containing more than others. Maintainingproper levels of cholesterol in the body has become an important factorin todays diet, since medical science has proven that certainafflictions such as hypothyroidism, diabetes and the intake of foodshaving a high cholesterol content may result in high levels ofcholesterol in the blood.

A condition which is associated with elevated levels of cholesterol,phospholipids, and/or triglycerides in the blood serum of mammals iscommonly referred to as hyperlipidemia (i.e. as used herein, referenceto hyperlipidemia is intended to be inclusive of bothhypercholesterolemia and hypertriglyceremia, and hence, compounds havinga hypolipidemic effect will exhibit activity to lower both cholesteroland triglyceride lipid levels). Hyperlipidemia can lead to serioushealth problems such as arthereosclerosis. We know that serumlipoprotein in mammals is composed of cholesterol together withtriglyceride, phospholipid and apoproteins. Lipoprotein is composed ofseveral fractions--the very low density lipoprotein (VLDL), the lowdensity lipoprotein (LDL) and the high density lipoprotein (HDL)depending on the specific gravity of the apoprotein components of thefraction. Medical evidence points to the VLDL and LDL fractions as beingassociated with atherosclerosis. In contrast, the HDL fraction appearsto carry cholesterol from the blood vessels to the liver where it isprocessed and excreted in the bile. As hyperlipidemic states increase inatherosclerosis the LDL cholesterol increases and HDL decreases.Effective hypolipidemic agents need to reverse this ratio since clinicaldata indicate that high HDL cholesterol and low LDL cholesterol protectsman from myocardial infarctions. Thus, it is highly desirable to treatmammals afflicted with hyperlipidemia so as to lower VLDL and LDLfractions and increase the HDL fractions.

It is not surprising to find that a number of compounds have beenproposed for the treatment of hyperlipidemia in mammals. Examplesinclude U.S. Pat. No. 4,499,303 which describes the use of a novel classof N-benzoylsulfamates and benzoylsulfonamides as useful hypolipidemicagents. U.S. Pat. No. 4,395,417 proposes the use of cyclic imides,diones, reduced diones and analogs as useful agents. Orotic acid hasbeen shown to decrease the plasma lipids blood level in rats.

U.S. Pat. No. 4,639,444 describes3,5-dialkyl-4,6-diaryltetrahydro-2H-1,3,5-thiadiazine-2-thionederivatives as useful hypolipidemic agents. U.S. Pat. No. 4,681,893teaches that certain trans-6-[2-(3- or 4-carboxamido-substitutedpyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and their ring opened acids arepotent hypolipidemic agents. Likewise, U.S. Pat. No. 4,351,844 describeshypocholesterolemic lactone compound and their free acids which arederived from the natural fermentation product mevinolin. More recently,the control of hyperlipidemia through the use of a class of4-pyrimidinecarboxylic acids has been described by Hall et al., J.Pharm. Sci. 74, 759 (1985).

In spite of the numerous compounds and methods which have been proposedfor the control of hyperlipidemia, the need remains for drugs havingenhanced lowering of elevated serum lipoprotein lipids.

Accordingly, it is the object of the present invention to provide aclass of hypolipidemic compounds having enhanced capability in loweringLDL cholesterol and elevating HDL cholesterol. This and other objects ofthe present invention will be more apparent from the discussion whichfollows.

SUMMARY OF THE INVENTION

The present invention provides a method of controlling hyperlipidemia inmammals which comprises administering to a mammal an amount effective tocontrol hyperlipidemia of a compound having hypolipidemic activity andthe structural formula: ##STR1## wherein R¹ is hydrogen, a C₁ to C₁₈alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substituted alkenyl,a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀ cycloalkyl orsubstituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substitutedcycloalkenyl, phenyl, a substituted phenyl, phenalkyl, cyano, --CO--R⁹or --Y--CO--R⁹ ;

R² is ##STR2##

R³ and R⁴ can be the same or different and are each the same as R¹ ;

R⁵, R⁶ and R⁷ can be the same or different and are each hydrogen, a C₁to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substitutedalkenyl, a C₁ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl orsubstituted cycloalkenyl phenyl or substituted phenyl, phenalkyl,--CO--R⁹, or --Y--CO--R⁹,

with the proviso that R⁵ and R⁶ together cannot be so bulky as to causethe compound to decompose;

R⁸ is hydrogen, a C₁ to C₅ alkyl, a C₄ to C₁₀ cycloalkyl, --CO--R⁹, or--Y--CO--R⁹ ;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substitutedalkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, aC₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl orsubstituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substitutedcycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the sameor different and are each hydrogen, a C₁ to C₅ alkyl or substitutedalkyl, phenyl or substituted phenyl;

R¹² is --CO, --COH, --CS, --CSH, or a C₁ to C₄ alkylene group; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene;

and the pharmaceutically acceptable salts, and mixtures thereof.

In addition, the present invention provides for pharmaceuticalcompositions for use in controlling hyperlipidemia in mammals whichcomprises a hypolipidemically effective amount of a compound havinghypolipidemic activity and a structural formula (I) or apharmaceutically acceptable salt thereof as shown above in combinationwith a pharmaceutically acceptable carrier.

As referred to herein, "hypolipidemic activity" is intended to refer tothe ability of the compounds of formula (I) to lower levels of serumcholesterol and/or triglycerides in mammals to which the compound isadministered.

Many of the above-described compounds which may be used as hypolipidemicagents are new, and hence, as a further embodiment of the presentinvention there is provided a novel class of compounds havinghypolipidemic activity and the structural formula: ##STR3## wherein R¹is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenylor substituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl orsubstituted cycloalkenyl, phenyl, a substituted phenyl, phenalkyl,cyano, --CO--R⁹ or --Y--CO--R⁹ ;

R³ and R⁴ may be the same or different and are each the same as R¹ ;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substitutedalkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, aC₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl orsubstituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substitutedcycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ And R¹¹ can be the sameor different and are each hydrogen, a C₁ to C₅ alkyl or substitutedalkyl, phenyl or substituted phenyl; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene; provided that R³ andR⁴ are not both hydrogen and further provided that neither R³ nor R⁴ ishydrogen when R¹ is phenyl.

A second class of novel hypolipidemic agents according to this inventionhave the structural formula: ##STR4## wherein R¹ is hydrogen, a C₁ toC₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substitutedalkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl orsubstituted cycloalkenyl, phenyl, a substituted phenyl, cyano,phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;

R⁵ and R⁶ can be the same or different and are each hydrogen, a C₁ toC₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substitutedalkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl orsubstituted cycloalkenyl, phenyl or substituted phenyl, phenalkyl,--CO--R⁹, or --Y--CO--R⁹, as to cause the compound to decompose;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substitutedalkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, aC₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl orsubstituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substitutedcycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the sameor different and are each hydrogen, a C₁ to C₅ alkyl or substitutedalkyl, phenyl or substituted phenyl; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene; and thepharmaceutically acceptable salts thereof, and mixtures thereof;

provided that R¹ is not phenyl or chlorophenyl when R⁵ is hydrogen, R⁶is CO--R⁹, and R⁹ is ethoxy or when R⁶ is hydrogen, R⁵ is --CO--R⁹, andR⁹ is ethoxy; and further provided that R¹ is not phenyl when R⁵ ishydrogen, R⁶ is --CO--R⁹, and R⁹ is methoxy or when R⁶ is hydrogen, R⁵is --CO--R⁹, and R⁹ is methoxy.

A third class of novel hypolipidemic agents according to this inventionhave the structural formula: ##STR5## wherein R¹ is hydrogen, a C¹ toC₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl or substitutedalkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ to C₁₀cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl orsubstituted cycloalkenyl, phenyl, a substituted phenyl, cyano,phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;

R⁷ is hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substitutedalkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀cycloalkenyl or substituted cycloalkenyl, phenyl or substituted phenyl,phenalkyl, --CO--R⁹, or --Y--CO--R⁹,

R⁸ is hydrogen, a C₁ to C₅ alkyl, a C₄ to C₁₀ cycloalkyl, --CO--R⁹, or--Y--CO--R⁹ ;

R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substitutedalkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, aC₁ to C₅ alkoxy or substituted alkoxy, a C₄ to C₁₀ cycloalkyl orsubstituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl or substitutedcycloalkenyl, --NHC₆ C₅, --NR¹⁰ R¹¹ wherein R¹⁰ and R¹¹ can be the sameor different and are each hydrogen, a C₁ to C₅ alkyl or substitutedalkyl, phenyl or substituted phenyl;

R¹² is --CO, --COH, --CS, --CSH, or a C₁ to C₄ alkylene group; and

Y is a C₁ to C₁₀ alkylene or substituted alkylene;

with the proviso that when R⁸ is hydrogen and R⁷ is ethoxy, R¹ is notphenyl, chlorophenyl, methoxyphenyl, or n-butyl.

Pharmaceutically acceptable salts and mixtures of the above-describedcompounds are expected to have similar activity.

DETAILED DESCRIPTION OF THE INVENTION

We have found that the above-described compounds of formulas (I) through(IV) effectively lower serum lipids in mammals. The term mammals as usedherein is intended in its normal sense, and hence is inclusive of notonly mice, rats, dogs, cats, horses, pigs, sheep, cows and otheranimals, but humans as well. Through the use of the hypolipidemic agentsof the present invention, we observed the inhibition of activity of therate limiting enzyme of cholesterol synthesis (HMG CoA reductase) aswell as the lowering of the acyl CoA cholesterol acyl transferase(cholesterol ester), acetyl CoA carboxylase (fatty acid), snglycerol-3-phosphate acyl transferase and phosphatidylatephosphohydrolase (triglyceride) and heparin induced lipoprotein lipase(release of triglycerides for apoproteins).

The hypolipidemic agents of the present invention afford reduction inboth serum cholesterol and triglycerides and can be used in lower dosageamounts than commercially available agents such as nicotinic acidderivatives, clofibrate, cholestyramine and cholestipol. Through the useof the agents of the present invention we have observed significantincreases in HDL-cholesterol and reduced levels of LDL cholesterol withan acceleration of lipid excretion via the feces with clearance oflipids from the blood compartment and tissues, e.g. the aorta wall.

As used herein, the terms "alkyl", "alkenyl", "cycloalkenyl","cycloalkyl" and "alkoxy" refer to carbon containing substituents thatmay be straight chain or branched. The terms "substituted alkyl","substituted alkenyl", "substituted alknyl","substituted cycloalkyl","substituted cycloalkenyl" and "substituted alcoxy" include thosesubstituted with at least one common functional substituent selectedfrom but not limited to the group consisting of alkoxy, oxo, alkoxycarbonyl, halogen, nitro, aryl, carbamoyl, amino, amido, acyloxy,hydroxy, carboxy, alkylthio, sulfoxide, sulfone, thiol, sulfonyl,sulfano, phosphono and silyl. Thus, examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, and npentyl. Examples ofalkoxy groups include methoxy and ethoxy. Exemplary of suitablecycloalkyl groups are cyclobutyl, cyclopentyl or cyclohexyl.

The terms "substituted phenyl" and "substituted phenoxy" refer to thepresence on the aromatic ring of at least one common functionalsubstituent selected from but not limited to the group of C₁ to C₅alkyl, substituted C₁ to C₅ alkyl, C₁ to C₅ alkoxy, benzoyl, alkanoyl,alkoxy carbonyl, halogen, nitro, carbamoyl, amino, amido, acyloxy,hydroxy, carboxy, alkylthio, sulfoxide, sulfone, thiol, sulfonyl,sulfano, phosphono and silyl.

Halogen groups may be selected from bromine, chlorine, fluorine andiodine, and preferably from chlorine and bromine.

Our invention provides a method for treating hypolipidemia in mammals byadministering a hypolipidemically effective amount of a compound offormula (I). Examples of compounds of formula (I) wherein R² is (a) arethose wherein R¹ is selected from the group consisting of phenyl,halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbonatoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbonatoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R³and R⁴ may be the same or different and are each selected from the groupconsisting of hydrogen, alkylcarbonyl wherein the alkyl group has from 1to 5 carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to5 carbon atoms, and N-phenylcarbamoyl. Specific compounds of formula (I)wherein R² is (a) include4-phenyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,-4-phenyl-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-phenyl-1-N-phenylcarbamoyl-1,2,4-triazolidine-3,5-dione, 4-phenyl-1-ethoxycarbonyl-1,2,4-triaZolidine-3,5-dione,4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione,4-n-butyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione,4-methyl-1,2,4-triazolidine-3,5-dione,4-phenyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine 3,5-dione,4-(4-methoxyphenyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-phenylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-methoxyphenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-I-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-n-propylcarbonyl-I,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-benzoyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione, and4-n-butyl-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-phenyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-phenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-n-butyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,and pharmaceutically acceptable salts and mixtures thereof.

Compounds of formula (I) wherein R² is (b) include those wherein R¹ isselected from the group consisting of phenyl, halophenyl, alkylphenylwherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenylwherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, andalkyl having from 1 to 5 carbon atoms; and R⁵ and R⁶ are the same ordifferent and are each selected from the group consisting of hydrogen,alkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms,alkylcarbonyl wherein the alkyl group has from 1 to 5 carbon atoms,phenoxycarbonyl, carbamoyl and substituted carbamoyl. It is appreciatedthat, if R⁵ and R⁶ are too bulky, such as in the case when both arearomatic, the compound wherein R² is (b) may decompose. Thus thosecompounds are intended to be excluded from the invention.

Exemplary of compounds of formula (I) wherein R² is (b) are3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione,3-phenyl-6-ethoxycarbonyl-1,3,5triazabicyclo[3.1.0]hexane-2,4-dione,3-(4-methoxyphenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.10]hexane-2,4-dione,4-n-butyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione,3-phenyl-6-methoxycarbonyl-1,3,5-triazabicyclo[ 3.1.0]hexane-2,4-dioneand pharmaceutically acceptable salts and mixtures thereof.

Compounds of formula (I) wherein R² is (c) include those wherein R¹ isselected from the group consisting of phenyl, halophenyl, alkylphenylwherein the alkyl group has from 1 to 5 carbon atoms, alkoxyphenylwherein the alkoxy group has from 1 to 5 carbon atoms, nitrophenyl, andalkyl having from 1 to 5 carbon atoms; R⁷ is an alkoxy having from 1 to5 carbon atoms or phenoxy; and R⁸ is hydrogen or a C₁ to C₅ alkyl; andR¹² is --CO. Exemplary of the compounds of formula (I) wherein R² is (c)are 3-phenyl-6-ethoxycarbonyl-1,3,5-triazine-2,4(1H,3H)-dione;3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-triazine-2,4(1H,3H)-dione; andpharmaceutically acceptable salts and mixtures thereof.

According to a further aspect, our invention provides novel compounds offormula (II) as defined above with the proviso that provided that bothR³ and R⁴ are not hydrogen and that R¹ is not phenyl when either R³ andR⁴ is hydrogen and further provided that R⁹ is not --NHC₆ H₅ when R¹ isphenyl. Our invention further provides novel compounds of formula (III)as defined above provided that R¹ is not phenyl or chlorophenyl when R⁵is hydrogen, R⁶ is --CO--R⁹, and R⁹ is ethoxy or when R⁶ is hydrogen, R⁵is --CO--R⁹, and R⁹ is ethoxy; and further provided that R¹ is notphenyl when R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is methoxy or when R⁶is hydrogen, R⁵ is --CO--R⁹, and R⁹ is methoxy. Novel compounds offormula (IV) as defined above are also provided with the proviso thatwhen R⁸ is hydrogen and R⁷ is ethoxy, R¹ is not phenyl, chlorophenyl,methoxyphenyl, or n-butyl.

Included compounds from within the class defined by formula (II) arethose wherein R¹ is selected from the group consisting of halophenyl,alkylphenyl wherein the alkyl group has from 1 to 5 carbon atoms,alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbon atoms, andnitrophenyl; and R³ and R⁴ are each selected from the group consistingof hydrogen, alkylcarbonyl wherein the alkyl group has from 1 to 5carbon atoms, alkoxycarbonyl wherein the alkoxy group has from 1 to 5carbon atoms, and a carbamoyl or substituted carbamoyl with the provisothat both R³ and R⁴ are not both hydrogen.

Exemplary of novel hypolipidemic compounds of formula (II) are4-phenyl-1-methylcarbonyl-1,2,4-triazolidine 3,5-dione,4-phenyl-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4 -triazolidine-3,5-dione,4-(4-methoxyphenyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1,2-diethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1,2-di-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione, 4-(4-chlorophenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-benzoyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-benzoyl-1,2,4-triazolidine-3,-dione,4-(4-nitrophenyl)-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-I-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-ethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-benzoyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-n-propylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-n-pentylcarbonyl-1,2,4-triazolidine-3,5-dione,4-n-butyl-1-n-butylcarbonyl-1,2,4-triazolidine-3,5-dione, and 4-n-butyl-1-trichloromethylcarbonyl-1,2,4-triazolidine-3,5-dione,4-phenyl-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione4-(4-chlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-n butyl-1 -(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-phenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-chlorophenyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-methoxyphenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-(4-nitrophenyl)-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,4-D-butyl-1,2-bis-(3,4,5-trimethoxybenzoyl)-1,2,4-triazolidine-3,5-dione,and pharmaceutically acceptable salts and mixtures thereof.

Novel compounds from within the class defined by formula (III) includethose wherein R¹ is selected from the group consisting of phenyl,halophenyl, alkylphenyl wherein the alkyl group has from 1 to 5 carbonatoms, alkoxyphenyl wherein the alkoxy group has from 1 to 5 carbonatoms, nitrophenyl, and alkyl having from 1 to 5 carbon atoms; and R⁵and R⁶ may be the same or different and are each selected from the groupconsisting of hydrogen and alkoxycarbonyl wherein the alkoxy group hasfrom 1 to 5 carbon atoms.

Exemplary of novel hypolipidemic compounds of formula (III) are3-(4-methoxyphenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione,3-n-butyl-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione,3-(4-nitrophenyl)-6-ethoxycarbonyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dioneand pharmaceutically acceptable salts and mixtures thereof.

Compounds from within the class defined by formula (IV) include thosewherein R¹ is selected from the group consisting of halophenyl,nitrophenyl and alkoxyphenyl wherein the alkoxy group contains from 1 to5 carbon atoms but is not ethoxy when R¹ is chlorophenyl.

As noted, the pharmaceutically acceptable salts of the compounds offormulas (I) through (IV) can be used. These salts may be acid additionsalts formed from inorganic or organic, e.g. hydrochlorides, sulfates,phosphates, benzoates or acetates, or salts formed with bases, e.g.alkali metal salts such as sodium or potassium salts.

The amount of hypolipidemically active compound as defined by formulas(I) through (IV) (including esters and pharmaceutically acceptable saltsthereof) which is required for the treatment of patients suffering fromelevated lipid levels will vary with the route of administration, thecondition of the patient under treatment and is ultimately at thediscretion of the attending physician. However, a suitable dose of theactive compound is in the rang of from about 1 to about 100 mg/kg bodyweight per day; preferably from about 4 to about 16 mg/kg daily. Thus,for example, when administered to man (of approximately 70 kg bodyweight) in multiple daily doses, a typical unit or subdose of the activecompound is about 150 mg.

The form of the dose is not critical and may be formulated for oral,buccal, parenteral or rectal administration or in a form suitable foradministration by inhalation or inefflation. Oral administration ispreferred.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example mucilage of starch orpolyvinylpyrrolidone; fillers, for example, lactose, microcrystallinecellulose or maize-starch; lubricants, for example, magnesium stearateor stearic acid; disintegrants, for example, potato starch,croacarmellose sodium or sodium starch glycollate; or wetting agentssuch as sodium lauryl sulphate. The tablets may be coated according tomethods well known in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or anothersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup or carboxymethyl cellulose;emulsifying agents, for example, sorbitan mono-oleate; nonaqueousvehicles (which may include edible oils), for example, propylene glycolor ethyl alcohol; and preservatives, for example, methyl or propylp-hydroxybenzoates or sorbic acid. Suitably, a 1% aqueous solution ofcarboxymethylcellulose may be employed.

The compounds of formulas (I) through (IV) or their salts may also beformulated as suppositories, e.g. containing conventional suppositorybases such as cocoa butter or other glycerides.

For buccal administration, the composition may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formulas (I) through (IV) and their physiologicallyacceptable acid addition or basic salts may be formulated for parenteraladministration by injection or continuous infusion and may be presentedin unit dose form in ampoules, or in multi-dose forms with an addedpreservative.

The compositions may take such forms as suspensions, solutions, oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilizing, and/or dispersing agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water,before use.

It will therefore be appreciated that the compounds of formulas (I)through (IV) or their pharmaceutically acceptable salts, may be used inthe manufacture of a medicament for the treatment of human or animalsubjects suffering from hyperlipidemia.

EXPERIMENTAL

Melting points and boiling points are uncorrected. Infrared spectra wererecorded on a Beckman Acculab 10 spectrophotometer. Ultraviolet spectrawere obtained on a Beckman DBG spectrophotometer. ¹ H NMR spectra wererecorded on a Varian EM-360A spectrometer. Mass spectra were determinedon an AEI-902 mass spectrometer at the Research Triangle Institute ofMass Spectrometry, Research Triangle Park, N.C. Elemental analyses wereperformed by Integral Microanalytical Laboratories, Raleigh, N.C. andDesert Analytics, Phoenix, Ariz.

Generally, derivatives of 1,2,4-triazolidine-3,5-diones (Compounds offormula (I)(a) and (II)) may be synthesized by reacting 4-substituted1,2,4-triazolidine-3,5-diones synthesized by the stepwise procedure ofCookson, Gupte, Stevens, and Watts, Org. Syn. 1871, 51, 121, withcarboxylic acid anhydrides or alkoxy chloroformates wherein the alkoxygroup has from 1 to 5 carbon atoms in the presence of sodium hydride, oraryl isocyanates in the presence of sodium hydride. 1- and 1,2-alkylsubstituted derivatives can be made by reacting 4-substituted1,2,4-triazolidine-3,5-diones with alkyl halides or cycloalkyl halidesin the presence of a base, e.g. KOH. This latter method can also be usedto prepare alkenyl, cycloalkenyl and alkynyl derivatives so long as themultiply bonded group is not directly attached to the ring nitrogen. Toattach a phenyl in the R³ or R⁴ position, phenylhydrazine should be usedto cyclize the triazolidine-3,5-dione ring.

Derivatives of 1,3,5-triazine-2,4-(1H,3H)-diones (Compounds of formula(I)(c) and (IV) may be synthesized by heating a solution of a compoundof formula (I)(b) or (III) in chlorobenzene at reflux for 2 weeks.

The following specific examples illustrate the preparation of compoundsdefined by formulas (I) through (IV) and are according to the invention,but are not to be construed as limiting the scope thereof.

Preparation of Compounds of Formula (I)(a) and (II)

The 4-substituted 1,2,4-triazolidine-3,5-diones were prepared by thestepwise procedure of Cookson, Gupte, Stevens and Watts, Org. Synth.1971, 51, 121.

General Procedure for the Synthesis of the1-Alkyl-carbonyl-4-substituted-1,2,4-triazolidine-3,5-diones: To astirred suspension of the 4-substituted 1,2,4-triazolidine-3,5-dione (30mmol) in 150 to 200 ml of chloroform at room temperature was addeddropwise the carboxylic acid anhydride or other appropriate acylatingagent (450 mmol). The reaction mixture was stirred at room temperatureor heated under reflux, as required, for one to five days. The reactionmixture was filtered to remove the 1-acylated 4-substituted1,2,4-triazolidine-3,5-dione and unreacted1,2,4-triazolidiine-3,5-dione. This solid mixture was not always presentdepending on the anhydride used in the reaction. Treatment of thefiltered solid with water removed the unreacted1,2,4-triazolidine-3,5-dione to give the1-alkylcarbonyl-1,2,4-triazolidine-3,5-dione, which was purified byrecrystallization from ethanol:water. The filtrate was washed with three100 ml portions of water and three 80 ml portions of 10% sodiumcarbonate. The carbonate washings were acidified with concentratedhydrochloric acid to precipitate an additional quantity of the1-alkylcarbonyl-4-substituted-1,2,4-triazolidine-3,5-dione.

Preparation of 1-Methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione:To a suspension of 5.3 g (30 mmol) of4-phenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroform was addeddropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydridewith stirring. The reaction mixture was stirred at room temperature forfive days. The reaction mixture was filtered to remove a whiteprecipitate which was washed with 30 ml of chloroform to give 3.55 g(54.0 %) of 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione aswhite solid, m.p. 215°-218.5° C. The filtrate was washed with three 100ml portions of water and three 80 ml portions of 10% sodium carbonate.The carbonate washings were acidified with concentrated hydrochloricacid. No precipitate was formed. The chloroform solution was dried (Na₂SO₄) and evaporated under reduced pressure to give a liquid residuecontaining acetic anhydride. The filtered solid was recrystallized from95% ethanol to yield pure1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: m.p.216.5°-218.5° C.; IR Nujol) 1726, 1710, 1688 cm⁻¹ (CO); ¹ H NMR (60 MHz,CDCl₃)δ7.90 (s, 5H) 2.55(s, 3H). Found: C, 54.5; H, 4.2: N, 19.4. C₁₀ H₉N₃ O₃ requires C, 54.8; H, 4.2; N, 19.4.

Preparation of1-Methylcarbonyl-4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione: To asuspension of 6.38 g (30 mmol) of4-(4-chlorophenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroformwas added dropwise over a 15 minute period 45.9 g (450 mmol) of aceticanhydride with stirring. The reaction mixture was stirred at roomtemperature for five days. The reaction mixture was filtered. Thefiltrate was washed with three 100 ml portions of water and three 80 mlportions of 10% sodium carbonate. The carbonate washings were acidifiedwith concentrated hydrochloric acid to yield a precipitate of thetriazolidine-3,5-dione product. In some instances a precipitate, whichwas presumably the sodium salt of the triazolidine-3,5-dione, formed inthe sodium carbonate washings prior to acidification. In these instancesthe precipitate was filtered from the carbonate washings and dissolvedin hot water prior to acidification. The chloroform solution was dried(Na₂ SO₄) and evaporated under reduced pressure to give a liquid residuecontaining acetic anhydride. The filtered triazolidine-3,5-dione wasrecrystallized from 95% ethanol to yield pure1-methylcarbonyl-4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione as awhite solid: m.p. 201°-203° C.; IR (Nujol) 1729, 1710, and 1690 cm⁻¹(CO); ¹ H NMR (60 MHz, CDCl₃ δ7.5(m, 4 H), 2.5 (s, 3 H). Found: C,47.31;H, 3.10; N, 16.63; M⁺ (70eV) 253.0253. C₁₀ H₈ N₃ O₃ Cl requires C,47.35; H, 3.18; N, 16.57; M⁺ 253.0254.

General Procedure for the Synthesis of the1,2-Dialkylcarbonyl-4-substituted-1,2,5-triazolidine-3,5-diones: To astirred mixture of the 4-substituted 1,2,4-triazolidine-3,5-dione (30mmol) and lead diacetate trihydrate (60 mmol) in 200 ml of chloroformwas added dropwise the carboxylic acid anhydride or appropriateacylating agent (450 mmol). The reaction mixture was stirred at roomtemperature until all the solids had dissolved. The solution was washedwith three 100 ml portions of water and three 100 ml portions of 10%sodium carbonate. Acidification of the carbonate washings withconcentrated hydrochloric acid did not produce a precipitate. Thechloroform solution was dried (Na₂ SO₄) and evaporated under reducedpressure to give a solid-liquid mixture. The mixture was filtered andthe solid was recrystallized from alcohol:water to yield the pure1,2-dialkylcarbonyl-4-substituted-1,2,4-triazolidine-3,5-dione. Acetatesalts such as sodium acetate can be used in place of lead diacetatetrihydrate in the reaction mixture.

Preparation of1,2-Dimethylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: To a mixtureof 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione and 22.7 g(60 mmol) of lead diacetate trihydrate in 200 ml of chloroform was addeddropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride.The mixture was stirred at room temperature. After 25 hours the paleyellow solution was washed with three 100 ml portions of water and three75 ml portions of 10% sodium carbonate. The carbonate washings wereacidified with concentrated hydrochloric acid. No precipitate wasproduced. The chloroform solution was dried (Na₂ SO₄) and evaporatedunder reduced pressure to give a solid-liquid residue. The residue wasfiltered and the filtered solid was washed with 25 ml of 95% ethanol togive 2.75 g (35.1%) of the 1,2,4-triazolidine-3,5-dione product as awhite solid. An additional quantity of the product precipitated from theethanol filtrate. This solid was filtered to give an additional 1.20 g(15.3%) of the 1,2,4=triazolidine-3,5-dione product (50.4% total yield).The solids were recrystallized from 95% ethanol to give pure1,2-dimethylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: m.p.169°-170.5° C.; IR (Nujol) 1750, 1732 (shoulder), 1714 (shoulder) cm⁻¹(CO); ¹ H NMR (60 MHz, CDCl₃)δ7.80(s, 5H), 2.55 (s, 6H); Found: C, 55.2;H, 4.45; N, 16.0; C₁₂ H₁₁ N₃ O₄ requires C, 55.2; H, 4.2; N, 16.0.

Preparation of1,2-Dimethylcarbonyl-4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione:To a mixture of 1.00 g (4.83 mmol) of4-methoxyphenyl-1,2,4-triazolidine-3,5-dione and 3.80 g (10 mmol) oflead diacetate trihydrate in 40 ml of chloroform was added dropwise overa 10 minute period 7.70 g (75 mmol) of acetic anhydride. The solutionwas stirred at room temperature for five hours. The clear solution waswashed three times with 20 ml portions of water and three times with 15ml portions of 10% sodium carbonate. The sodium carbonate washings wereacidified with concentrated hydrochloric acid. No precipitate wasobtained. The chloroform solution was dried (Na₂ SO₄) and evaporated todryness under reduced pressure to give a solid-liquid residue. Theresidue was washed with five ml of 95% ethanol and recrystallized frommethanol to give pure1,2-dimethylcarbonyl-4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione: mp. 148°-150° C.; IR (Nujol) 1710, 1750 cm⁻¹ (CO); ¹ H NMR (300 MHz,CDCl₃)δ7.37-6.98 (m, 4H), 3.84 (s, 3H), 2.65(s, 6H); Found: C, 53.4; H,4.4; N, 14.4. C₁₃ H₁₃ N₃ O₅ requires C, 53.6; H, 4.5; N, 14.4.

Preparation of1,2-di-n-Pentylcarbonyl-4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione:To a mixture of 1.00 g (4.83 mmol) of4-methoxyphenyl-1,2,4-triazolidine-3,5-dione and 3.80 g (10 mmol) oflead diacetate trihydrate in 40 ml of chloroform was added dropwise overa 10 minute period 7.70 g (75 mmol) of hexanoic anhydride. The solutionwas stirred at room temperature for five hours. The clear solution waswashed three times with 20 ml portions of water and three times with 15ml portions of 10% sodium carbonate. The sodium carbonate washings wereacidified with concentrated hydrochloric acid. No precipitate wasobtained. The chloroform solution was dried (Na₂ SO₄) and evaporated todryness under reduced pressure to give a solid-liquid residue. Theresidue was washed with five ml of 95% ethanol and recrystallized frommethanol to give pure1,2-di-n-pentylcarbonyl-4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione:m.p. 88°-90° C.; lR (Nujol) 1742, 1710 cm⁻¹ (CO); ¹ H NMR (300 MHz,CDCl₃)δ7.36-6.97 (m, 4H), 3.83 (s, 3H), 2.97 (t, 4H), 1.76 (m, 4H), 1.35(m, 8H), 0.89 (distorted t, 6H); Found: C, 62.3; H, 7.0; N, 10.3. C₂₁H₂₉ N₃ O₅ requires C, 62.5; H, 7.3; N, 10.4.

Preparation of1,2-Diethylcarbonyl-4(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione: To amixture of 1.00 g (4.50 mmol) of4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione and 3.80 g (10 mmol) oflead diacetate trihydrate in 40 ml of chloroform was added dropwise overa 10 minute period 9.80 g (75 mmol) of propanoic anhydride. The solutionwas stirred at room temperature for five hours. The clear solution waswashed three times with 20 ml portions of water and three times with 15ml portions of 10% sodium carbonate. The sodium carbonate washings wereacidified with concentrated hydrochloric acid. No precipitate wasobtained. The chloroform solution was dried (Na₂ SO₄) and evaporated todryness under reduced pressure to give a solid-liquid residue. Theresidue was washed with five ml of 95% ethanol and recrystallized frommethanol to give1,2-diethylcarbonyl-4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione: m.p.140°-142° C.; IR (Nujol) 1750, 1705 cm⁻¹ (CO); ¹ H NMR (300 MHz,CDCl₃)δ8.41-7.24 (m, 4H), 3.03 (q, 4H), 1.28 (t, 6H); Found: C, 49.9; H,4.0; N, 16.7. C₁₄ H₁₄ N₄ O₆ requires C, 50.2; H, 4.2; N, 16.8.Preparation of1,2-Di-n-pentylcarbonyl-4-n-butyl-1,2,4-triazolidine-3,5-dione: To amixture of 1.00 g (6.37 mmol) of 4-n-butyl-1,2,4-triazolidine-3,5-dioneand 4.60 g (12 mmol) of lead diacetate trihydrate in 40 ml of chloroformwas added dropwise over a 10 minute period 19.5 g (91 mmol) of hexanoicanhydride. The solution was stirred at room temperature for five hours.The clear solution was washed three times with 20 ml portions of waterand three times with 15 ml portions of 10% sodium carbonate. The sodiumcarbonate washing were acidified with concentrated hydrochloric acid. Noprecipitate was obtained. The chloroform solution was dried (Na₂ SO₄)and evaporated to dryness under reduced pressure to give a solid-liquidresidue. The residue was washed with five ml of 95% ethanol andrecrystallized from methanol to give pure1,2-di-n-pentylcarbonyl-4-n-butyl-1,2,4-triazolidine-3,5-dione: m.p.88°-89° C.; IR (Nujol) 1736, 1715 cm⁻¹ (CO); ¹ H NMR (300 MHz,CDCl₃)δ2.91 (t, 4H), 1.77-1.29 (m, 18H), 0.89 m, 9H): Found: C, 60.95:H, 8.9: N, 11.85. C₁₆ H₃₁ N₃ O₄ requires C, 61.15; H, 8.9; N, 11.9.

Preparation of Compounds of Formula (I)(b) and (III)

Methyl diazoacetate was synthesized by the procedure of Searle, U.S.Pat. No. 2,490,714 (1949) and Chem. Abstr. 1950, 44, 3519. The4-substituted 3-H-1,2,4-triazoline-3,5-diones were prepared by thestepwise procedure of Cookson, Gupte, Stevens, and Watts, Orq. Synth.,1971, 51, 121. t-butyl hypochlorite was prepared using the method ofTeeter and Bell, Orq. Synth. Coll., Vol. IV, 1963, 125. Ethyldiazoacetate was purchased commercially.

Reactions of diazoalkanes with 3-H-1,2,4-triazoline-3,5(4H)-diones havebeen previously described. See Izydore, R.A., McLean, S., J. Am. Chem.Soc. 1975, 97, 5611.

General Procedure for the Synthesis of the6-Alkyoxycarbonyl-3-substituted-1,3,5-triazalcyclo[3.1.0]hexane-2,4-diones;

To a solution of the 3-H-1,2,4-triazoline-3,5(4H)-dione (20 mmol) indichloromethane (200 ml) at 0° C. was added dropwise over 10 minutes thediazoalkane, with stirring. Stirring was continued until the red colorof the triazolinedione had faded. The solution was then filtered andevaporated to dryness under reduced pressure. The resulting solid waspurified by recrystallization by first dissolving it in hot carbontetrachloride-chloroform (1:1), and then cooling the solution to roomtemperature, and finally by adding petroleum ether (b.p. 40°-60° C.) orhexane dropwise with swirling to precipitate a compound of formula(I)(b) and (III).

Preparation of6-Ethoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione: Toa solution of 1.5 g (8.5 mmol) of4-phenyl-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml of dichloromethaneat 0° C. was added dropwise over 10-20 minutes 0.97 g (8.5 mmol) ofethyl diazoacetate, with stirring. Gas evolution was noted. The deep redsolution was allowed to warm to room temperature, and stirring wascontinued overnight. The resulting amber solution was evaporated todryness under reduced pressure to yield 2.17 g (98%) of the crudebicyclic product. The product was purified by heating it in 20 ml of hotcarbon tetrachloride, adding chloroform dropwise until the solid haddissolved, cooling the solution to room temperature, and addingpetroleum ether (40°-60° C.) dropwise with swirling to precipitate pure6-ethoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione:m.p. 175°-177° C. (decomp.); IR (Nujol) 1745 cm⁻¹ (CO); ¹ H NMR (400MHz, CDCl₃)δ1.3 (3H, br m, CH₃), 3.8 (1H, br s, CH), 4.3 (2H, br m,OCH₂), and 7.5 (5H, m, Ph); ¹³ C NMR (100.5 MHz; CDCl₃ ; ¹ H decoupled)13.0-14.5 (overlapping s, CH₃), 62.0-65.5 (overlapping s, OCH₂ and CH),124.5-127.5 and 128.0-131.5 (overlapping s, Ph), and 152.8-165.0 (broverlapping s, CO). Found: C, 55.3; H, 4.1; N, 16.0; M⁺ (70 eV), 261.C₁₂ H₁₁ N₃ O₄ requires C, 55.2; H, 4.25; N, 16.1; M⁺, 261.

Preparation of6-Methoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione:To a solution of 2.05 g (11.7 mmol) of4-phenyl-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml of dry ethylacetate at 0° C. under nitrogen was added dropwise over a 20 minuteperiod 1.10 g (11 mmol) of methyl diazoacetate, with stirring. The deepred solution was kept at 0° C. for one hour and warmed to roomtemperature. Stirring was continued overnight. The pale yellow solutionwas filtered and evaporated to dryness under reduced pressure to give alight yellow solid. The solid was purified by heating it in 10 ml of hotcarbon tetrachloride, adding chloroform (approximately 10 ml) to themixture dropwise until the solid dissolved, cooling the solution to roomtemperature, and adding petroleum ether (b.p. 40°-60° C.) dropwise withvigorous mixing. The precipitated solid was filtered and dried to yield2.50 g (92%) of pure 6-methoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione as a white solid: M.P. 176°-177° C. (decomp.).IR (Nujol) 1740 cm⁻¹ (CO); ¹ H NMR (100 MHz; CDCl₃ 3.75 (1H, br s, CH),3.88 (3 H, br m, OMe), and 7.45 (5H, m, Ph); ¹³ C NMR (25.2 MHz; CDCl₃ ;¹ H decoupled)δ54.0 (br, OMe and CH), and 123-126 and 128-131 (br,overlapping s, Ph); Found: C, 53.1; H, 3.8; N, 16.85; M⁺ (70 eV), 247.C₁₁ H₉ N₃ O₄ requires C, 53.4; H, 3.6; N, 17.0; M⁺, 247.

Preparation of6-Ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazabicyclo[3.1.0]-hexane-2,4-dione:To a solution of 2.33 g (11 mmol) of4-(4-chlorophenyl)-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml ofdichloromethane at 0° C. under nitrogen was added dropwise over a 20minute period 1.25 g (11 mmol) of ethyl diazoacetate. The deep redsolution was kept at 0° C. for one hour and allowed to warm to roomtemperature. Stirring was continued overnight. The pale yellow solutionwas filtered and evaporated to dryness under reduced pressure to give3.08 g (95%) of the crude bicyclic product as a light yellow solid. Thesolid was purified by heating it in 3 ml of hot carbon tetrachloride,adding chloroform (approximately 25 ml) dropwise until the soliddissolved, cooling the solution to room temperature, and addingpetroleum ether (b.p. 40°-60° C.) dropwise with mixing. The precipitatedsolid was filtered and dried to yield pure6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dioneas a white solid: M.p. 174°-176° C. (decomp.). IR (Nujol) 1740 cm⁻¹(CO); ¹ H NMR (100 MHz; CDCl₃)δ1.3 (3H, br m, CH₃), 4.25(1H, br m, CH),4.35(2H br m, OCH₂, and 7.5 (4H, m, 4-CDClH₄) ¹³ C NMR (100.5 MHz; CDCl₃; ¹ H decoupled) 13.0-14.5 (overlapping CH₃), 62.0-65.5 (overlappings,CH and OCH₂), and 133.2-137.5 (overlappings, 4-ClC₆ H₄), and 148.0-166.0(br overlappings, CO). Found: C, 48.6; H, 3.4; N, 14.0; M⁺ (70 eV),295.0362. C₁₂ H₁₀ N₃ O₄ requires C, 48.75; H, 3.4; N, 14.2; M⁺,295.0360.

Preparation of6-Ethoxycarbonyl-3-(4-methoxyphenyl)-1,3,5-triazabicyclo[3.1.0]-hexane-2,4-dione:To a solution of 2.28 g (11 mmol) of4-(4-methoxyphenyl)-3H-1,2,4-triazoline-3,5(4H)-dione in 100 ml ofdichloromethane at 0° C. under nitrogen was added dropwise over a 20minute period 1.25 g (11 mmol) of ethyl diazoacetate. The deep redsolution was kept at 0° C. for one hour and allowed to warm to roomtemperature. Stirring was continued overnight. The pale yellow solutionwas filtered and evaporated to dryness under reduced pressure to give2.89 g (90%) of the crude bicyclic product as a light yellow solid. Thesolid was purified by heating it in 10 ml of hot carbon tetrachloride,adding chloroform (approximately 10 ml) dropwise until the soliddissolved, cooling the solution to room temperature, and addingcyclohexane dropwise with mixing. The precipitated solid was allowed tosit for two hours, filtered, washed with five ml of carbontetrachloride, and dried to yield pure6-ethoxycarbonyl-3-(4-methoxyphenyl)-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dioneas a white solid: m.p. 175°-178° C. (decomp.). IR (Nujol) 1740 cm⁻¹(CO); ¹ H NMR (60 MHz; CDCl₃)δ1.3 (3H, br m, CH₂ CH₃), 3.7 (3H, br m,OMe), 4.3 (3H, br m, CH and OCH₂), and 6.4-7.6 (4H, m, 4-MeO--C₆ H₄).Found: C, 53.65; H, 4.7; N, 14.4. C₁₃ H₁₃ N₃ O₅ requires C, 53.6; H,4.5; N, 14.4.

Preparation of6-Ethoxycarbonyl-3-n-butyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione:To a solution of 1.73 g (11 mmol) of3-n-butyl-3H-1,2,4-triazoline-3,5-(4H)-dione in 100 ml ofdichloromethane at 0° C. under nitrogen was added dropwise over a 20minute period 1.25 g (11 mmol) of ethyl diazoacetate. The deep redsolution was kept at 0° C. for one hour and allowed to warm to roomtemperature. Stirring was continued overnight. The pale yellow solutionwas filtered and evaporated to dryness under reduced pressure to give2.38 g (90%) of the crude bicyclic product as a light yellow solid. Thesolid was purified by dissolving it in 20 ml of carbon tetrachloride andadding cyclohexane dropwise with mixing to effect precipitation. Theprecipitated solid was filtered and dried to yield pure6-ethoxycarbonyl-3-n-butyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione asa white solid: m.p. 94°-96° C. (decomp.); IR (Nujol) 1740 cm⁻¹ (CO); ¹ HNMR (60 MHz; CDCl₃)δ0.6-1.9 (10H, br m, CH₃ (CH₂)₂ and CH₃ CH₂ O), 3.5(2H, br m, CH₂ N), and 4.2 (2H, br m, OCH₂). Found: C, 49.6; H, 6.4; N,17.1. C₁₀ H₁₅ N₃ O₄ requires C, 49.8; H, 6.3; N, 17.4.

Preparation of Compounds of Formula (I)(c) and (IV)

General Procedure for the Synthesis of the6-alkoxycarbonyl-3-aryl-1,3,5-triazine-2,4(1H,3H)-diones: A solution ofthe bicyclic diaziridine (formula (I)(b) or (III)) (20 mmol) inchlorobenzene (250 ml) was heated at reflux for two weeks. The reactionmixture was cooled to room temperature, and the precipitate was removedby filtration. The filtered solid was stirred in methylene chloride (200ml) for 30 min and filtered to remove thetriazolo[1,2-a]triazole-1,3,5,7-tetraone (25-35%). The methylenechloride solution was evaporated to dryness under reduced pressure togive the crude triazine. Purification was accomplished byrecrystallization from chloroform-cyclohexane or chloroform-petroleumether (b.p. 40°-60° C.). If necessary the recrystallized product wasfurther purified by preparative t.l.c. on silica gel. It was necessaryto heat the purified product under vacuum to drive off the purificationsolvents.

Preparation of6-Ethoxycarbonyl-3-phenyl-1,3,5-triazine-2,4(1H,3H)-dione: A solution of7.0 g (26.8 mmol) of6-ethoxycarbonyl-3-phenyl-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dione in250 ml of chlorobenzene was heated to reflux for two weeks during whichtime a precipitate slowly formed. After cooling the reaction mixture toroom temperature, the precipitate was filtered to yield 3.3g of crudesolid. The solid was stirred in 200 ml of dichloromethane for 30 minutesand filtered. The filtered solid was washed with an additional 50 ml ofdichloromethane to give 1.5 g (35%) of2,6-diphenyltriazolo[1,2-a]triazole-1,3,5,7-tetraone: m.p. greater than310° C. The combined methylene chloride washings were evaporated underreduced pressure to yield 1.5 g (21%) of crude6-ethoxycarbonyl-3-phenyl-1,3,5-triazine-2,4(1H,3H)-dione: m.p.158°-164° C. (decomposition). The 1,3,5-triazinedione product waspurified as follows: A quantity weighing 1.00 g of the1,3,5-triazinedione was heated in 20 ml of boiling carbon tetrachloride.To the hot mixture was added in 5 ml portions 20 ml of chloroform todissolve the solid. The hot solution was filtered, and the filtrate wascooled to room temperature. The cool filtrate was added to 200 ml ofcyclohexane at room temperature with mixing to precipitate 0.0 g of anoff-white solid: m.p. 168°-170° C. In place of cyclohexane, petroleumether (b.p. 40°-60° C.) may be substituted. It was generally observedthat addition of cyclohexane to the carbon tetrachloride-chloroformfiltrate led to the formation of a gummy precipitate. The off-whitesolid was heated at 110° C. in a heating pistol to drive off theremaining recrystallization solvents to yield pure6-ethoxycarbonyl-3-phenyl-1,3,5-triazine-2,4(1H,3H)-dione as a whitesolid: M.p. 168°-170° C. (decomp.). IR (Nujol) 3440 (NH), 1746 (CO),1779 (CO), and 1607 cm⁻¹ (C═N); UV_(max) (MeOH) 257 nm (ε3700); ¹ H NMR(60 MHz, acetone-d₆)δ1.37 (3H, t, CH₃), 4.39 (2H, q, OCH₂), and 7.31 (5H, m, Ph). Found: C, 55.05; H, 4.2; N, 16.5; M⁺ (70 eV), 261.0747; C₁₂H₁₁ N₃ O₄ requires C, 55.2; H, 4.3; N, 16.1; M³⁰ , 261.0749.

Preparation of6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazine-2,4(1H,3H)-dione: Asolution of 6.0 g (20.3 mmol) of6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazabicyclo[3.1.0]hexane-2,4-dionein 250 ml of chlorobenzene was heated at reflux for two weeks duringwhich time a precipitate slowly formed. After cooling the reactionmixture to room temperature, the precipitate was filtered to yield 2.13g of crude solid. The solid was stirred in 200 ml of dichloromethane for30 minutes and filtered. The filtered solid was washed with anadditional 50 ml of dichloromethane to give 1.0 g (25%) of2,6-di-(4-chlorophenyl)-triazolo[1,2-a]triazol-1,3,5,7-tetraone, m.p.greater than 310° C. The combined methylene chloride washings wereevaporated under reduced pressure to yield 1.08 g (18.0%) of crude6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazine-2,4(1H,3H)-dione:m.p. 191°-196° C. (decomposition). The 1,3,5-triazinedione product wasrecrystallized by heating 0.50 g of the product in 60 ml of boilingcarbon tetrachloride, with stirring. A total of 55 ml of chloroform wasthen added in five ml portions to dissolve the solid. The hot solutionwas filtered, and then filtrate was cooled to room temperature. Thecooled filtrate was added dropwise to 200 ml of cyclohexane withstirring to precipitate 0.21 g of an off-white solid: m.p. 203°-205° C.It has generally observed that addition of cyclohexane to the carbontetrachloride-chloroform filtrate led to the formation of a gummyprecipitate. In place of cyclohexane petroleum ether (b.p. 40°-60° C.)may be substituted. In an alternate procedure 0.80 g of the product wasdissolved in 25 ml of cold acetate. The solution was filtered, and thefiltrate was added slowly with swirling to precipitate 0.45 of anoff-white solid: m.p. 191°-196° C. The recrystallized product waspurified by preparative thin-layer chromatography (TLC) as follows: Asample of the recrystallized product weighing 0.35 g (1.2 mmol) wasdissolved in 2.0 ml of HPLC grade ethyl acetate and applied in a thinstreak 1.0 cm high across the bottom of 20 cm×20 cm silica TLC plates.Twelve plates were used. The plates were developed in a closed chamberusing glacial acetic acid as the mobile phase. The plates wereair-dried. Analysis under UV light (254 nm) revealed the presence of twocomponents having R_(f) values of 1.00 and 0.90, respectively. Each ofthe separated components was scraped from the plates and combined. Eachof the components was then extracted into 50 ml of dichloromethane,filtered, and the solvent removed under reduced pressure to give a solidresidue. The solid corresponding to the slower moving component (R_(f)=0.90) weighed 0.15 g: m.p. 212°-215° C. This solid was recrystallizedby dissolving it in 20 ml chloroform-carbon tetrachloride (50:50) andadding the resulting solution to 100 ml of cyclohexane. The precipitatewas filtered to give 0.090 g of pure6-ethoxycarbonyl-3-(4-chlorophenyl)-1,3,5-triazine-2,4(1H,3H)-dione as awhite solid: M.P. 214°-215° C. (decomp.). IR (Nujol) 3430 (NH), 1759(CO), 1740 (CO), 1666 (CO), and 1590 cm⁻¹ (C═N); UV_(max) (MeOH) 260 nm3900); ¹ H NMR (60 MHz, acetone-d₆)δ1.39 (3H, t, CH₃), 4.38 (2H, q,OCH₂), 4.8 (1H, br s, NH), and 7.37 (4H, m, 4-ClC₆ H₄). Found: C, 48.65;H, 3.3; N, 14.0; M⁺ (70 eV), 295.0362; C₁₂ H₁₀ N₃ O₄ C₁ requires C,48.7; H, 3.4; N, 14.2; M⁺, 295.0360.

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts of the compounds ofgeneral formulas (I) through (IV), using conventional methods.

Testing of Normal Mice

The following compounds were tested for their hypolipidemic activity inCF₁ mice.

    ______________________________________                                        Compound No.                                                                            Name                                                                ______________________________________                                        Parent    1,2,4-triazolidine-3,5-dione                                        A         4-phenyl-1-methylcarbonyl-1,2,4-triazolidine-3,5-                             dione                                                               B         4-phenyl-1,2-dimethylcarbonyl-1,2,4-triazolidine-                             3,5-dione                                                           C         4-phenyl-1-ethoxycarbonyl-1,2,4-triazolidine-3,5-                             dione                                                               D         4-(4-chlorophenyl)-1-methylcarbonyl-1,2,4-                                    triazolidine-3,5-dione                                              E         4-phenyl-1,2,4-triazolidine-3,5-dione                               F         4-(4-methoxyphenyl)-1,2,4-triazolidine-3,5-dione                    G         4-(4-n-butyl)-1,2,4-triazolidine-3,5-dione                          H         4-(4-nitrophenyl)-1,2,4-triazolidine-3,5-dione                      I         4-phenyl-1-N-phenylcarbamoyl-1,2,4-triazolidine-                              3,5-dione                                                           J         4-(4-chlorophenyl)-1,2,4-triazolidine-3,5-dione                     K         4-methyl-1,2,4-triazolidine-3,5-dione                               L         3-(4-chlorophenyl)-6-ethoxyacarbonyl-1,3,5-                                   triazabicyclo[3.1.0]hexane-2,4-dione                                M         3-phenyl-6-ethoxycarbonyl-1,3,5-                                              triazabicyclo[3.1.0]hexane-2,4-dione                                N         3-phenyl-6-ethoxycarbonyl-1,3,5-triazine-                                     2,4(1 .sub.--H,3 .sub.--H)-dione                                    O         3-(4-chlorophenyl)-6-ethoxycarbonyl-1,3,5-                                    triazine-2,4(1H,3 .sub.--H)-dione                                   P         4(4-methoxyphenyl)-1,2-dimethylcarbonyl-1,2,4-                                triazolidine-3,5-dione                                              Q         4.(4-methoxyphenyl) -1,2-diphenylcarbonyl-1,2,4-                              triazolidine-3,5-dione                                              R         4.(4-methoxyphenyl)-1,2 diethylcarbonyl-1,2,4-                                triazolidine-3,5-dione                                              S         4-(4-nitrophenyl)-1,2 diethylcarbonyl -1,2,4-                                 triazolidine-3,5-dione                                              T         4-(4-n-butyl)-1,2 dipentylcarbonyl-1,2,4-                                     triazolidine-3,5-dione                                              U         4-(4-chlorophenyl)-1,2-dimethylcarbonyl-1,2,4-                                triazolidine-3,5-dione                                              V         4-(4-chlorophenyl)1-pentylcarbonyl (2 .sub.--H)-1,2,4-                        triazolidine-3,5 dione                                              ______________________________________                                    

Compounds A-V as defined above, were suspended in an aqueous 1 percentcarboxymethylcellulose (CMC) solution and homogenized. Each of the soprepared compounds were administered to a group of six CF₁ male mice,each weighing approximately 25 grams, intra-peritioneally for 16 days.Each of these compounds were provided in a dosage of 20 mg/kg/d ip. OnDays 9 and 16 blood was obtained by tail vein bleeding. The blood serumso obtained was separated by centrifugation for three minutes. Serumcholesterol levels were determined by a modification of theLiebermann-Burchard reaction (Ness, Clin. Chim. Acta., Vol. 10, 229[1964]). Serum triglyceride levels were determined on Day 16 by use ofthe Fisher, Hycel Triglyceride Test Kit.

In addition to the above-described treated mice, an untreated controlgroup of six mice were similarly tested on Days 9 and 16 to determinetheir serum cholesterol and trigylceride blood levels. Based on theresults obtained for the untreated control group, the percent control,based on serum cholesterol and serum triglyceride levels of the treatedmice compared to the untreated mice, was obtained. Table 1 reports thispercent control, including standard deviation, indicating the level ofconfidence of these numbers.

                  TABLE 1                                                         ______________________________________                                                    Serum Cholesterol*                                                                           Serum Triglyceride                                 Compound No.                                                                              Day 9     Day 16   Day 16                                         ______________________________________                                        Parent      81        79       73                                             A           67 ± 5 61 ± 6                                                                              48 ± 6                                      B           70 ± 6 64 ± 5                                                                              61 ± 5                                      C           73 ± 7 69 ± 5                                                                              62 ± 6                                      D           73 ± 4 64 ± 6                                                                              55 ± 7                                      E           71 ± 5 48 ± 3                                                                              68 ± 6                                      F           75 ± 5 56 ± 4                                                                              58 ± 3                                      G           71 ± 6 69 ± 5                                                                              79 ± 8                                      H           73 ± 5 66 ± 5                                                                              47 ± 5                                      I           79 ± 7 74 ± 6                                                                              68 ± 6                                      J           90 ± 5 58 ± 4                                                                              43 ± 4                                      K           88 ± 6 67 ± 5                                                                              89 ± 5                                      L           74 ± 3 56 ± 5                                                                              66 ± 7                                      M           62 ± 6 57 ± 5                                                                              59 ± 6                                      N           63 ± 6 54 ± 5                                                                              51 ± 2                                      O           63 ± 4 57 ± 4                                                                              55 ± 6                                      P           76        57       49                                             Q           67        86       75                                             R           62        63       62                                             S           72        36       62                                             T           69        49       53                                             U           72        51       51                                             V           77        52       42                                             1% Carboxymethyl-                                                                         100 ± 6                                                                              100 ± 5                                                                             100 ± 7                                     cellulose                                                                     ______________________________________                                         *Reported as a percentage of serum cholesterol or serum triglyceride leve     as control + or - the standard deviation.                                

Testing of Hyperlipidemic Mice

A group of six CF₁ male mice (about 25 g) were placed on a commercialdiet (U.S. Biochemical Corporation BAsal Atherogenic Test Diet) whichproduced a "hyperlipidemic" state. That is, the average serumcholesterol level in the group of treated mice was raised from 122 to375 mg percent and triglyceride levels were raised from 137 to 367mg/dL.

Upon reaching these hyperlipidemic levels the mice were administeredCompounds A, J M and N in a concentration of 20 mg/kg/d [LD₅₀ value inmice as single injection IP>500 mg/kg for these compounds]intraperitoneally for 14 days while continuing the hyperlipidemic diet.On Day 12, serum cholesterol and serum triglyceride levels were measuredin accordance with the procedure of Example 6. The following resultswere obtained:

                  TABLE 2                                                         ______________________________________                                                    Percent of Control                                                Compound    Serum Cholesterol                                                                            Serum Triglyceride                                 ______________________________________                                        A           41             40                                                 J           46             49                                                 M           46             54                                                 N           50             46                                                 Diet-Hyperlipidemic                                                                       100            100                                                ______________________________________                                    

Serum Testing of Normal Rats

Test solution of Compounds A, F, J, M, N and O were suspended in anaqueous solution of 1% CMC, homogenized and administered orally to sixSprague-Dawley male rats, which each weighted approximately 350 grams.Administration of the compounds was by an intubation needle. The ratswere each fed with 20 milligrams of Compounds A, F, J, M, N and O perkilogram of body weight per day for 14 days. Similarly, sixSprague-Dawley male rats of approximately the same weight (that used fortesting F weighed approximately 160 grams) were fed similar volumes ofthe same aqueous 1% CMC solution without the active agents, also orally,administered by intubation needle. In addition, as a control, a similargroup of six male Sprague-Dawley rats were untreated.

On Days 7 and 14, blood was obtained from each of the rats of the threegroups by tail vein bleeding. The blood obtained was separated bycentrifugation for three minutes. Serum cholesterol and triglyceridelevels were determined in accordance with the procedure of Example 6.The following results were obtained:

                  TABLE 3                                                         ______________________________________                                                     Percent of Control                                                            Serum Cholesterol                                                                           Serum Triglyceride                                 Compound     Day 7    Day 14   Day 7  Day 14                                  ______________________________________                                        A            89       69       62     48                                      F            77       66       87     81                                      J            59       60       61     52                                      M            70       36       36     54                                      N            71       67       61     53                                      O            84       60       82     77                                      1% Carboxymethyl                                                                           100      100      100    100                                     cellulose                                                                     ______________________________________                                    

Formulations

    ______________________________________                                        A. Tablet                                                                     Ingredient      Amount per tablet                                             ______________________________________                                        Active Compound 150.0 mg                                                      Lactose         100.0 mg                                                      Corn Starch      15.0 mg                                                      Magnesium stearate                                                                             1.0 mg                                                       ______________________________________                                    

The active compound is finely ground and intimately mixed with thepowdered excipients (lactose, corn starch, and magnesium stearate). Theformulation is then compressed in a die to produce the tablet.

    ______________________________________                                        B. Coated Tablet                                                              Ingredient      Amount per tablet                                             ______________________________________                                        Core                                                                          Active Compound 150.0 mg                                                      Corn Starch     25.0 mg                                                       Magnesium stearate                                                                             2.0 mg                                                       Coating                                                                       Lactose         200.0 mg                                                      Corn Starch     50.0 mg                                                       Gelatin         10.0 mg                                                       ______________________________________                                    

The active ingredient and starch are granulated with water and dried.Magnesium stearate is added to the dried granules. Lactose and starchare granulated with 10% w/v aqueous solution of gelatin and dried.Magnesium stearate is added to the dried coating granules. Thegranulated core is compressed with the granulated coating in aconventional compression molding press.

    ______________________________________                                        C. Capsule                                                                    Ingredient     Amount per Capsule                                             ______________________________________                                        Active Compound                                                                              150.0 mg                                                       Lactose        200.0 mg                                                       Magnesium stearate                                                                            10.0 mg                                                       ______________________________________                                    

The finely ground active compound is mixed with the powdered excipientsand packed into a two part gelatin capsule.

    ______________________________________                                        D. Suspension                                                                 Ingredient            Amount per mL                                           ______________________________________                                        Active Compound       75.0    mg                                              Sodium lauryl sulfate 25.0    mg                                              Hydroxypropylmethylcellulose                                                                        100.0   mg                                              Sucrose               50.0    mg                                              Flavor and Color      q.s.                                                    Water                 q.s. 1.0                                                                              mL                                              ______________________________________                                    

The sodium lauryl sulfate, hydroxypropylmethylcellulose, flavor andcolor are triturated with the active compound. This mixture is thenblended with 0.5 ml water and sucrose, and additional water is added tomake the total volume 1.0 ml of suspension.

The hypolipodemic compounds of the present invention when administeredto mammals provide for a significant increase in the HDL cholesterolcontent (Table 4), coupled with a desirable reduction of the LDLcholesterol content. Furthermore, the very low density lipoprotein,which generally is high in triglyceride and neutral lipid content, andwhich carries these lipids to the tissues from the liver, is markedlyreduced by the agents.

                  TABLE 4                                                         ______________________________________                                        The cholesterol content of serum lipoprotein of                               Sprague-Dawley Rats treated orally for 14 days at 20 mg/kg/day                with compounds A,F,J,M,N and O is tabulated in Table 4.                                          Percent of                                                           VLDL cho-                                                                              Control LDL HDL cho-                                                 lesterol cholesterol lesterol                                       ______________________________________                                        Control 1%  100        100         100                                        CMC compound                                                                  A           44         74          441                                        F           59         78          141                                        J           98         43          194                                        M           71         67          340                                        N           50         87          409                                        O           27         78          113                                        ______________________________________                                    

We claim:
 1. A pharmaceutical compound for controlling hyperlipidemia inmammals having the following structural formula: ##STR6## wherein R¹hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ to C₁₈ alkenyl orsubstituted alkenyl, a C₂ to C₁₈ alkynyl or substituted alkynyl, a C₄ toC₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀ cycloalkenyl orsubstituted cycloalkenyl, phenyl, a substituted phenyl, cyano,phenalkyl, --CO--R⁹ or --Y--CO--R⁹ ;R⁵ and R⁶ be the same or differentand are each hydrogen, a C₁ to C₁₈ alkyl or substituted alkyl, a C₂ toC₁₈ alkenyl or substituted alkenyl, a C₂ to C₁₈ alkynyl or substitutedalkynyl, a C₄ to C₁₀ cycloalkyl or substituted cycloalkyl, a C₄ to C₁₀cycloalkyl or substituted cycloalkenyl, phenyl or substituted phenyl,phenalkyl, --CO--R⁹, or --Y--CO--R⁹, with the proviso that R⁵ and R⁶ arenot both aromatic; R⁹ is hydrogen, a C₁ to C₅ alkyl or substitutedalkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl orsubstituted alkynyl, phenyl or substituted phenyl, phenoxy orsubstituted phenoxy, a C₁ to C₅ alkoxy or substituted alkoxy, a C₄ toC₁₀ cycloalkyl or substituted cycloalkenyl, --NHC₆ H₅, --NR¹⁰ R¹¹wherein R¹⁰ and R¹¹ can be the same or different and are each hydrogen,a C₁ to C₅ alkyl or substituted alkyl, phenyl or substituted phenyl; andY is a C₁ to C₁₀ alkylene or substituted alkylene; and thepharmaceutically acceptable salts thereof, and mixtures thereof;provided that R¹ is not phenyl, chlorophenyl, methoxyphenyl or n-butylwhen R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is ethoxy or when R⁶ ishydrogen, R⁵ is --CO--R⁹, and R⁹ is ethoxy; and further provided that R¹is not phenyl when R⁵ is hydrogen, R⁶ is --CO--R⁹, and R⁹ is methoxy orwhen R⁶ is hydrogen, R⁵ is --CO--R⁹, and R⁹ is methoxy.
 2. Thepharmaceutical compound of claim 1 wherein R¹ is selected from the groupconsisting of phenyl, halophenyl, alkylphenyl wherein the alkyl grouphas from 1 to 5 carbon atoms, alkoxyphenyl wherein the alkoxy group hasfrom 1 to 5 carbon atoms; and R⁵ and R⁶ may be the same or different andare each selected from the group consisting of hydrogen andalkoxycarbonyl wherein the alkoxy group has from 1 to 5 carbon atoms. 3.A pharmaceutical compound for controlling hyperlipidemia in mammalshaving the following structural formula: ##STR7## wherein R¹ hydrogen, aC₁ to C₅ alkyl or substituted alkyl, a C₂ to C₅ alkenyl or substitutedalkenyl, a C₂ to C₅ alkynyl or substituted alkynyl, phenyl or asubstituted phenyl, phenyalkyl, --CO--R⁹ or --Y--CO--R⁹ ;R⁵ and R⁶ bethe same or different and are each hydrogen, a C₁ to C₅ alkyl orsubstituted alkyl, a C₂ to C₅ alkenyl or substituted alkenyl, a C₁ to C₅alkynyl or substituted alkynyl, phenyl or substituted phenyl, phenalkyl,--CO--R⁹, or --Y--CO--R⁹, with the proviso that R⁵ and R⁶ are not botharomatic; R⁹ is hydrogen, a C₁ to C₅ alkyl or substituted alkyl, a C₂ toC₅ alkenyl or substituted alkenyl, a C₂ to C₅ alkynyl or substitutedalkynyl, phenyl or substituted phenyl, phenoxy or substituted phenoxy, aC₁ to C₅ alkoxy or substituted alkoxy, or --NHC₆ H₅ and Y is a C₁ to C₅alkylene or substituted alkylene; and the pharmaceutically acceptablesalts, and mixtures thereof; provided that R' is not phenyl,chlorophenyl, methoxyphenyl or n-butyl when R⁵ is hydrogen, R⁶ is--CO--R⁹, and R⁹ is ethoxy or when R⁶ is hydrogen, R⁵ is --CO--R⁹, andR⁹ is ethoxy; and further provided that R¹ is not phenyl when R⁵ ishydrogen, R⁶ is --CO--R⁹, and R⁹ is methoxy or when R⁶ is hydrogen, R⁵is --CO--R⁹, and R⁹ is methoxy.
 4. A pharmaceutical composition for usein controlling hyperlipidemia in mammals which comprises ahypolipidemically effective amount of a compound having hypolipidemicactivity and a structural formula as defined in claim 1 in combinationwith a pharmaceutically acceptable carrier.